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Immunosuppressive therapy in myelodysplastic syndromes
Table 3. Other immunosuppressive therapy regimens.
Author Year
DeegHJetal. 2002
PlatzbeckerU 2005
Treatment N and treatment
schedule
Etanercept,25mg,2x/weeks.c. 14 for 16 weeks (increased to 3x/week
if no response at 8 weeks).
SirolimusPO6mgloadingdose 19
followed by 2 mg once daily adjusted to target blood concentration of 3–12 ng/ml for ≥ 3 months
Mycophenolate mofetil 1 g 10 twice a day PO + prednisone
0.5 mg/Kg/d PO tapering
to 10 mg/d for 12 weeks
IPSS risk category
Low: 29% Intermediate-1: 36% Intermediate-2: 29% High: 7%
Low: 11% Intermediate-1: 68% Intermediate-2: 21%
Not reported
FAB/WHO classification
RA: 43% RARS: 14% CMML: 14% RAEB-I/II: 29% RA: 5% RARS: 11% RCMD: 53% RAEB-I: 26% RAEB-II: 5% RARS: 60% RCMD: 40%
RARS: 3% CMML: 9% RCMD: 16% RAEB-I: 31% RAEB-II: 34% Not reported
Outcomes
No CR or PR HI-E: 33% TI: 0%
PR: 5%
HI-E: 5%
Adverse Ref. events
4 infectious AE (20) (2 ≥ grade 3)
10 AE in 8 patients; (39)
1 case of grade IV thrombocytopenia
et al.
Remacha AF et al.
2010
NoCRsorPRs 5AEin10 (40) HI-E: 56% patients
ScottBL 2010 AZA75mg/m2ondays 20
TI: 33% (1 infectious ≥ grade 3) Low:9% RA:6% CR:28% 37AE≥grade3 (32)
et al.
Sloand, EM 2010 et al.
1-7 every 28 days
+ Etanercept 25 mg s.c. on days 8, 11, 15, and 18
Alemtuzumab 10 31 mg/d IV for 10 days
Intermediate-1: 38% Intermediate-2: 31% High: 22%
Low: 7% Intermediate-1: 71% Intermediate-2: 23%
PR: 6% HI-E: 44%
in 32 patients (3 infectious)
AE: adverse events; ATG: anti-thymocyte globulin; AZA: azacitidine; CMML: chronic myelomonocytic leukemia; CR: complete remission; CTCAE: Common Terminology Criteria for Adverse Events; HI-E: hematologic improvement-erythroid; IPSS: International Prognostic Scoring System; PR: partial remission; RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB: refractory anemia with excess blasts; RCMD: refractory cytopenia with multilineage dysplasia; TI: transfusion independence.
ment decisions, two recent phase II clinical trials on the transforming growth factor (TGF)-β pathway inhibitors luspatercept and sotatercept have shown that the presence of ≥15% ringed sideroblasts or of a SF3B1 mutation was predictive of a higher rate of treatment response.45-47
Given the small sample sizes of most studies, the differ- ent treatment regimens used, and the various diagnostic techniques employed, there was a high degree of hetero- geneity among included studies. However, sensitivity analyses accounting for the type of IST as well as a 'one- study removed' analysis, found no significant impact of this heterogeneity on the overall results of the meta-analy- sis. The study by Xiao et al.13 demonstrated a significantly higher ORR and rate of HI-E and TI compared to other studies studying the application of ATG + CsA. This can be explained by the fact that in the study by Xiao et al.13 patients were strictly selected to have a high chance of responding to IST. Patients were required to have low risk MDS (IPSS score equal or less 1.0) and either expression of the HLA-DR15 allele or a BM cellularity of less than 30%, or an abnormal immune index of BM T lymphocytes. Furthermore, patients were excluded if they had >5% marrow myeloblasts or a poor risk karyotype or a diagno-
sis of concurrent non-hematologic malignancy. By exclud- ing the study by Xiao et al.,13 from the analysis, hetero- geneity in the subgroup analysis of studies examining ATG + CsA decreased significantly. This demonstrates that by strict selection of MDS patients, who are predicted to benefit from IST, the response to IST can be significant- ly increased.
While a randomized, placebo-controlled, double-blind- ed design is the gold standard of clinical studies, the het- erogenous patient population in terms of demographic, clinical (e.g. prior treatments), and molecular co-factors makes such a trial design challenging. As expected, this systematic review and meta-analysis confirmed the lack of published prospective, randomized controlled trials of IST in MDS. In this meta-analysis, 20 out of 22 included studies were single arm clinical trials or prospective cohort studies. As the Downs and Black checklist had been orig- inally developed for the evaluation of multi-arm studies, several of its quality criteria such as randomization, equal distribution of confounding variables among study groups, and blinding were not applicable to the majority of the studies in our meta-analysis. However, when elim- inating items from the modified Downs and Black check-
CR: 23%
PR: 3%
HI (any cell line): 39% TI: 32%
84 AE in 31 (19) patients
of which
28 ≥grade 3
(13 patients with ≥grade 3
infectious AE)
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